Radiation Therapy, Skin (Integument) Ulcer


Article Author:
Biagio Manna


Article Editor:
Jeffrey Cooper


Editors In Chief:
Mark Dreyer
Dustin Constant
Melanie Violand


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
6/3/2019 6:51:49 PM

Introduction

In 2016, approximately 1,700,000 new cases of cancer were diagnosed. It is estimated that the number of new cases of cancer is 484 per 100,000. The number of patients living beyond their cancer diagnosis is estimated to be 14.5 million in 2014 and is expected to be 19 million by 2024.

It is estimated that half of the patients with cancer will receive radiation therapy, with skin injuries due to radiation therapy occurring in approximately 95%. Also, accidental and occupational exposure to radiation contributes to a number of patients with radiation injuries and skin.

Management of acute or chronic skin injuries due to ionizing radiation is a complex challenge with injuries ranging from acute redness to chronic wounds that cannot be visualized.[1][2][3]

Chronic manifestations of radiation injuries may include radiation-induced fibrosis of the skin, nonhealing ulcers, osteoradionecrosis, compromised muscle flaps, and dehiscence of surgical closures.[4][5]

Etiology

A constant state of skin renewal that occurs approximately every 26 days makes the skin more vulnerable than any other organ to ionizing radiation injury. Ionizing radiation creates free radicals and reactive oxygen intermediates that lead to DNA and protein damage, as well as damage to cellular membranes of rapidly proliferating tissue. (Ruth Bryant and Denise Nix. Acute and Chronic Wounds, Current Management Concepts. 5th Edition. St. Louis, Missouri: Elsevier; 2016.)

Epidemiology

Skin injuries ranging from erythema to full chronic wounds occur in about 95% of patients who undergo radiation therapy. Occupational and accidental radiation exposure are also risk factors for radiation injury. The areas of the body that are more susceptible to radiation injury are the skin of the face, neck, trunk, and extremities.

Pathophysiology

There are 4 grades of radiation dermatitis and injury, ranging from erythema to necrotic ulcers.[6][7][8]

  • Faint erythema or dry desquamation characterize grade 1.
  • Grade 2 exhibits moderate to brisk erythema, patchy moist desquamation, and it is mostly confined to the skinfold creases. There may be moderate edema at the injured site.
  • Grade 3 consists of moist desquamation at sites other than skinfold creases; there may be bleeding the site of injury induced by minor trauma.
  • Grade 4 consists of skin necrosis or full thickness wounds. There may be spontaneous bleeding at the involved injured site.

As the effects of radiation to the skin are cumulative, there are more severe skin injuries toward the end of the radiation. The degree of injury depends mainly on the radiation intensity and the patient's tissue sensitivity to the radiation.

The concept of radiation recall involves the skin recalling a previous radiation exposure to a particular area when chemotherapeutic agents such as doxorubicin or docetaxel are administered within 2 months of the radiation treatment.

The primary pathophysiology of the injury is hypoxia due to the progressive obliteration of the microvasculature (progressive endarteritis) and fibrosis. Impaired wound healing in a previously irradiated area occurs due to disruption of the natural progression of the overlapping wound healing phases (hemostasis, inflammatory phase, proliferative phase, and remodeling phase). These disruptive can be grouped into several categories: cellular depletion, extracellular matrix (ECM) alteration, microvascular changes, cytokine and growth factor dysregulation.

  1. Cellular depletion: ionizing radiation affects cells in the G2 and M phases of the cell cycle, causing cellular apoptosis and impaired cellular proliferation and migration, causing an overall decrease in cells number.
  2. Alteration in cellular proliferation: Ionizing radiation effects collagen content and collagen strength, both decreased in irradiated wounds; an increase in matrix metalloproteinases (MMPs) unopposed by tissue inhibitors of MMPs (TIMP) will cause an abnormal degradation of ECM.
  3. Microvascular changes: This is caused by overall decreased in angiogenesis as well as physical changes of blood vessels caused by an increase in transforming growth factor-beta (TGF-beta) causing an increase in endothelial fibrosis with subsequent obliteration of the vessel lumen resulting in tissue hypoxia.
  4. Cytokines and growth factors dysregulation:
  • VEGF, bFGF: Angiogenic growth factors; decreased following radiation
  • Nitric oxide: Potent vasodilator and induces collagen deposition; decreased following radiation
  • TNF-alfa, IFN-gamma, IL-1, IL-6: Pro-inflammatory cytokines, prevent collagen deposition, induce TGF-beta1 through activation of macrophages/stromal cells; it is increased following radiation
  • TGF-beta1: Key mediator of fibrosis, promotes chemotaxis, signals fibroblasts proliferation, prevents collagen breakdown, promotes microvascular changes. It is decreased following radiation.

Histopathology

Pandya et al. examined specimens from 27 patients with OSCC (oral squamous cell carcinoma) who received radiation therapy involving the jaw and neck. He found significant tissue atrophy and severity of dysplasia, an increased presence of fibrinous exudative necrosis, vessel wall thickening, with oropharyngeal ectasia of the salivary gland. In addition, dense fibrosis with thick fibers was a common finding of post-radiation tissue in the same patients. Similar findings at other sites may be inferred regarding increased tissue fibrosis and hypoxia due to damaged microvasculature; glands within the dermal layer will also be affected similarly. These findings again confirmed the microvasculature thrombosis and tissue fibrosis characteristic of post-radiation skin changes that lead to eventual ulcers.[9]

History and Physical

At the time of the patient's evaluation, a thorough history should reveal the initial diagnosis for which radiation therapy was used, as well as the site of the radiation exposure, and finally the total amount of radiation that the patient has received. It is important to note the radiation dose as well as the timing of the onset of the observed skin changes.  Any associated chemotherapy will also need to be documented, in particular, the types of chemotherapeutic agents used.  Again, certain therapeutic agents were present as risk factors for radiation recall, as discussed above; some of the chemotherapeutic agents that will predispose to radiation recall are doxorubicin, docetaxel, paclitaxel, tamoxifen, methotrexate, to name a few. Chemotherapeutic agents such as doxorubicin, bleomycin, disulfiram, cisplatin, and mafenide acetate are also relative contraindications to hyperbaric oxygen treatment, a treatment modality that is often used as an adjuvant treatment for late effects of radiation skin changes such as ulcerations.

Overall, a thorough history will be important in providing documentation that will aid in choosing a specific treatment algorithm, especially if it involves hyperbaric oxygen treatment.

In addition to the physical exam that is customary for every patient evaluated for any disease process, there should be a particular focus on the presentation of the skin injury itself, as this will decide the treatment modality to be used, depending on the classification of radiation injury. Clinical manifestation of chronic radiation skin injury includes xerosis, hyperkeratosis, decreased or absent sweating, skin atrophy and dyspigmentation, as well as necrosis with full-thickness wounds, and others.

There should be a particular focus in identifying any contraindication to possible hyperbaric oxygen treatment, a treatment modality that is often used with late effects of radiation on the skin. A neck and head and exam is important, with a special focus on the eye for cataracts. The tympanic membranes should be evaluated for any scarring or other abnormalities that may make it hard for the pressure to equalize within the inner year. A chest radiograph to confirm the absence of any acute disease processes and for bullous diseases should be obtained given the high incidence of pneumothorax under more than one atmospheric pressure that is typical of a hyperbaric treatment protocol.

Evaluation

Evaluation of the patient with skin injury due to radiation treatment should include all relevant tests necessary for initiation of a specific treatment modality such as hyperbaric oxygen treatment; these tests would include a chest x-ray, a hemoglobin A1C, a sedimentation rate, and a complete blood count (CBC) if infection might be present.

Other tests may be ordered as applicable depending on the presentation of the patient at the time of the initial visit or if any complications were to arise during treatment.

Treatment / Management

In general, the treatment of radiation injury to the skin, acute, subacute or delayed, should reflect the extent of the injury itself,  keeping  in mind that necrotic tissue should be debrided, infection and inflammation should be managed properly, moisture management should not be ignored and continuous evaluation of the progression of the wound given the therapy employed should be done regularly with a treatment modality change depending on the status of the reepithelialization progress. In other words, standard wound management concepts should still be applied, with strict modifications given the etiology of the of the injury itself, ether just acute erythema at the skin or full thickness chronic wound.[10][11][12]

Management of Injury to the irradiated skin should begin with patient education in regards to skin care during the pre-radiation phase, post radiation phase and during the radiation treatment period. Education to the patient should include promotion of personal hygiene and wound hygiene, promotion of comfort, prevention of trauma to the affected skin, and management of radiation dermatitis.

Choices of cleanser and moisturizers and topical creams in radiation-induced skin injuries should reflect the extent of the injury itself. Products such as Natural Care Gel, Eucerin cream, Lubriderm, and corticosteroid cream can be used for erythema and dry desquamation.  If an infection is present topical antibiotic ointment such as Neosporin or silver sulfadiazine 1% can be used, although the need for systemic antibiotic should be assessed as well'

Additional management manifesting irradiation injuries to the skin can be broken down by the presenting clinical pathology:

  1. Radiation-induced fibrosis: Delanian showed that the use of pentoxifylline, a methylxanthine derivative, and alpha-tocopherol may cause partial reversibility of the fibrosis. In severe cases of fibrosis, surgical resection of the affected tissue may be indicated, with the reconstruction of the defect by a free flap or split thickness skin graft, with hyperbaric oxygen treatment as a possible adjuvant therapeutic agent as well.
  2. Nonhealing call service/soft tissue necrosis: initial treatment includes hyperbaric oxygen treatment and Pentoxyfilline and later surgical resection of the tissue followed by surgical reconstruction of the defect (
  3. Osteoradionecrosis/chondronecrosis: it usually affects irradiated facial bone (the mandible). Dental extraction and infection predispose osteoradionecrosis; management varies, from dental extraction before radiation therapy to pentoxifylline and vitamin E before dental extraction in post-irradiated tissue. Hyperbaric oxygen treatment has been used successfully for this type of chronic manifestation of radiation-induced injury

Hyperbaric oxygen treatment has one of the most frequent applications and delays radiation injuries, with up to one-third of patients treated with HBO2 for radiation injury in the United States. Even the mechanism of injury of ionizing radiation to be mainly hypoxia and increased district fibrosis, better oxygen treatment has been shown to increase angiogenesis and therefore improving oxygenation as well as reduce fibrosis, although this effect has not been fully investigated and explain.

Another mechanism of action of delayed radiation injury has been the negative impact of ionizing radiation on stem cells (Feldmeier J, Hyperbaric oxygen therapy and delayed radiation injury (soft tissue and bone necrosis. All serious investigations are now being pursued based upon luminary evidence that hyperbaric oxygen treatment increases the number of stem cells radiation injury site.

Prognosis

In general, the patient's prognosis will depend on several factors, mainly the extent of the radiation injury in terms of grades 1, 2, 3, or 4, as well as associated comorbidities.

Pearls and Other Issues

In conclusion, the management of radiation injury to the skin, especially grade 4 in which there are skin necrosis and full-thickness wounds, is complex with no accepted standards regarding specific modalities that are based upon irrefutable conclusions from RCT with a large number of patients. There are, however, accepted guidelines based on retrospective reviews that contain a small or large number of subjects. These reviews suggest, in general, that the treatment of radiation injuries, either acute, subacute or delayed, should follow good medical practices, with adaptations of known wound care principles to the problem at hand. For the management of full-thickness wounds due to delayed radiation injury, the accepted guidelines of management of necrotic tissue, prevention, and treatment of infections, management of wound exudate, and reevaluation of the treatment plan based upon observation of wound progress, should be coupled with patients education. This education should include everyday skin and wound care management and evaluation for methylxanthine derivatives in conjunction with hyperbaric oxygen treatment as well as the application of tissue containing stem cells, other live cells, as well as cytokines and growth factors, coupled with a healthy extracellular matrix.

Enhancing Healthcare Team Outcomes

Consultations for wound management in patients with radiation injury to the skin would generally require the input of specialists with expertise that may be beneficial to the patient depending on the location and the extent of the injury. Useful input by evaluation from plastic surgery, infectious disease, otorhinolaryngology, dermatology, and certified nurse specialists in wound managements with expertise in hyperbaric oxygen treatment will maximize the patient's potential for recovery.


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Radiation Therapy, Skin (Integument) Ulcer - Questions

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After radiation therapy to the chest, a patient develops a necrotic skin ulcer, which has failed to heal with conservative medical management for the past 3 months. What is the best treatment option?



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A 34-year-old male with a history of cancer of the right neck has undergone radical surgical excision of the tumor followed by chemotherapy with doxorubicin as well as extensive radiation therapy to the right neck and lower jaw. Six months later he develops a right molar abscess, which requires extraction. He is sent to the regional wound care and hyperbaric center for further evaluation for possible hyperbaric oxygen treatment (HBOT). Which of the following is false about HBOT?



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Which of the following is false in regards to radiation injury?



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Which of the following regarding radiation injury of the skin and its management is false?



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Which of the following is not true regarding the pathophysiology of impaired wound healing in radiation skin injuries grade 4 where an open wound is present?



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A 68-year-old male received radiation therapy to the right face and neck for treatment of oropharyngeal cancer in December 2016. Chemotherapy with paclitaxel was initiated in January 2017. Five days after the initiation of chemotherapy he noticed a rash on his right neck, which was pruritic and edematous. He was diagnosed with radiation recall at the site of the original radiation therapy. Which of the following is true about radiation recall?



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Hyperbaric oxygen treatment is an accepted treatment modality for ulcerations due to radiation injury to the skin because of which of the following?



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Radiation Therapy, Skin (Integument) Ulcer - References

References

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Naveed S,Thappa DM,Dubashi B,Pandjatcharam J,Munisamy M,Singh N, Mucocutaneous Adverse Reactions of Cancer Chemotherapy and Chemoradiation. Indian journal of dermatology. 2019 Mar-Apr;     [PubMed]
Nesi-Reis V,Lera-Nonose DSSL,Oyama J,Silva-Lalucci MPP,Demarchi IG,Aristides SMA,Teixeira JJV,Silveira TGV,Lonardoni MVC, Contribution of photodynamic therapy in wound healing: A systematic review. Photodiagnosis and photodynamic therapy. 2018 Mar;     [PubMed]
Krasnoselskiy NV,Simonova LI,Gertman VZ,Pushkar ES, Photodynamic therapy effect on healing of radiation skin ulcer infected with pseudomonas aeruginosa. Problemy radiatsiinoi medytsyny ta radiobiolohii. 2017 Dec;     [PubMed]
Skeik N,Porten BR,Isaacson E,Seong J,Klosterman DL,Garberich RF,Alexander JQ,Rizvi A,Manunga JM Jr,Cragg A,Graber J,Alden P,Sullivan T, Hyperbaric oxygen treatment outcome for different indications from a single center. Annals of vascular surgery. 2015 Feb;     [PubMed]

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